PROJECT SUMMARY Approximately 1 in 6 adolescents report regular binge alcohol consumption. The rapid growth in body weight during adolescence requires a concurrent increase in cardiac output, necessitating an increase in the size of the heart through cellular hypertrophy. However, the long-term effects of adolescent binge alcohol consumption on the heart are almost entirely unknown. Our preliminary data in a rat model show binge alcohol exposure in adolescence interferes with normal cardiac growth. Specifically, control rats grew normally in adolescence, their body weight and left ventricular end-diastolic volume (volume after the heart has filled with blood) both rising by ~45%. The alcohol binge rats had the same increase in body weight, but their end-diastolic volume increased by only half as much, severely limiting the ability of the adolescent heart to grow during this crucial period. In adults, binge alcohol consumption can reduce systolic function (weaker heart), in adolescence we observed the opposite: an increase in systolic function. This is likely a compensatory mechanism to maintain cardiac output, a smaller heart that works harder. Moreover, Doppler flow analysis revealed depressed diastolic function (relaxation) in the binge alcohol exposed rats. These preliminary data reveal clearly detrimental consequences of binge alcohol exposure in adolescence and raise two key questions. One, do these responses to binge alcohol exposure persist into adulthood and what are the consequences, and two, what molecular signaling is disrupted that lead to these whole-organ structural and functional changes? We will address these questions in the following aims. Aim 1 will assess the structural and functional consequences of adolescent binge alcohol consumption in the heart over time. Using our rat model of adolescent binge alcohol exposure, we will examine structure and function (using echocardiography, pathology, and cellular assays) to determine for how long the observed acute changes persist after cessation of alcohol exposure. In Aim 2 we will determine whether adolescent binge alcohol consumption sensitizes the adult heart to pathological stress or subsequent binge alcohol exposure. Rats with adolescent binge alcohol exposure will be allowed to mature to adults, and then subjected to either left anterior descending coronary ligation (resulting in myocardial infarction, aka a heart attack), or adult binge alcohol exposure. Lastly, Aim 3 will identify the signaling mechanisms involved in the cardiac structural and functional consequences of binge alcohol exposure. Heart growth, systolic function, and diastolic function are governed by known signaling mechanisms, such as growth factors (IGF-1), PI3K/Akt signaling, ?-adrenergic signaling, and titin phosphorylation. Using PCR, western blots, mass spectrometry, RNA-seq, and activity assays, we will identify which signaling pathways are disrupted by adolescent binge alcohol exposure to determine the mechanisms involved. These studies will discover consequences and mechanisms of our novel preliminary data showing significant effects of binge alcohol exposure in adolescent rats.